Dataset Information

A novel mutation in the β-spectrin gene causes the activation of a cryptic 5'-splice site and the creation of a de novo 3'-splice site.

ABSTRACT: The analysis of genes involved in hereditary spherocytosis, by next-generation sequencing in two patients with clinical diagnosis of the disease, showed the presence of the c.1795+1G>A mutation in the SPTB gene. cDNA amplification then revealed the occurrence of a consequent aberrant mRNA isoform produced from the activation of a cryptic 5'-splice site and the creation of a newly 3'-splice site. The mechanisms by which these two splice sites are used as a result of the same mutation should be analyzed in depth in further studies.

SUBMITTER: Salas PC

PROVIDER: S-EPMC4785562 | biostudies-other | 2015

REPOSITORIES: biostudies-other

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A novel mutation in the β-spectrin gene causes the activation of a cryptic 5'-splice site and the creation of a de novo 3'-splice site.

Salas Pilar Carrasco PC Rosales José Miguel Lezana JM Milla Carmen Palma CP Montiel Javier López JL Siles Juan López JL

Human genome variation 20150827

The analysis of genes involved in hereditary spherocytosis, by next-generation sequencing in two patients with clinical diagnosis of the disease, showed the presence of the c.1795+1G>A mutation in the SPTB gene. cDNA amplification then revealed the occurrence of a consequent aberrant mRNA isoform produced from the activation of a cryptic 5'-splice site and the creation of a newly 3'-splice site. The mechanisms by which these two splice sites are used as a result of the same mutation should be an ...[more]

PMID: 27081538

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Project description:BackgroundKleefstra syndrome (KS) is a rare autosomal dominant developmental disability, caused by microdeletions or intragenic mutations within the epigenetic regulator gene EHMT1 (euchromatic histone lysine N-methyltransferase 1). In addition to common features of autism, young adult regressive behaviors have been reported. However, the genetic downstream effects of the reported deletions or mutations on KS phenotype have not yet been completely explored. While genetic backgrounds affecting drug metabolism can have a profound effect on therapeutic interventions, pharmacogenomic variations are seldom considered in directing psychotropic therapies.MethodsIn this report, we used next-generation sequencing (exome sequencing and high-throughput RNA sequencing) in a patient and his parents to identify causative genetic variants followed by pharmacogenomics-guided clinical decision-making for making positive changes toward his treatment strategies. The patient had an early autism diagnosis and showed significant regressive behaviors and physical aberrations at age 23.ResultsExome sequencing identified a novel, de novo splice site variant NM_024757.4: c.2750-1G>T in EHMT1, a candidate gene for Kleefstra syndrome, in the patient that results in exon skipping and downstream frameshift and termination. Gene expression results from the patient showed, when compared to his parents, there was a significant decreased expression of several reported gene variants associated with autism risk. Further, using a pharmacogenomics genotyping panel, we discovered that the patient had the CYP2D6 nonfunctioning variant genotype *4/*4 that results in very low metabolic activity on a number of psychotropic drugs, including fluvoxamine which he was prescribed. As reported here, a change in psychotropic drugs and intense behavior therapies resulted in a significant reversal of the regressive behaviors and physical aberrations.ConclusionThese results demonstrate an individualized approach that integrated genetic information and behavior therapies, resulting in a dramatic improvement in regressive behaviors associated with KS.

Dataset Information

A novel mutation in the β-spectrin gene causes the activation of a cryptic 5'-splice site and the creation of a de novo 3'-splice site.

Publications

A novel mutation in the β-spectrin gene causes the activation of a cryptic 5'-splice site and the creation of a de novo 3'-splice site.

Similar Datasets

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